Topical Antibacterial Agents

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11.1 Overview

This chapter reviews topical antibacterial preparations used for cutaneous ulcers. The preparations discussed below are antiseptics.As stated in the previous chapter, these compounds ex- hibit non-selective toxicity, directed against any living tissue. The damage is not only to the pathogenic microorganisms but also, to a vari-

Topical Antibacterial Agents

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Contents

11.1 Overview 151 11.2 Oxidizing Agents 151 11.2.1 Hydrogen Peroxide 151 11.2.2 Potassium Permanganate 152 11.3 Iodines 152

11.3.1 Povidone-Iodine 152 11.3.2 Other Iodine Compounds 153 11.4 Chlorines 153

11.5 Silver 154

11.5.1 General Comments 154 11.5.2 Silver Sulfadiazine 154 11.6 Other Antiseptics 155 11.6.1 Antiseptic Dyes 155 11.6.2 Burow’s Solution 156 11.7 Conclusion 156

References 156

T

he germ is nothing; the terrain is everything.

(Attributed to Louis Pasteur on his deathbed, 1895)

’’

able extent, to the host’s cells. The degree of toxicity of these compounds is determined by the nature and concentration of their active ingre- dients, or by the presence or absence of addi- tional substances such as surfactants or alco- hol. Of the substances discussed, the only one that cannot be considered a pure antiseptic agent is silver sulfadiazine, since it contains an antibiotic component – sulfadiazine.

This chapter discusses the information and hypotheses relating to antiseptics and their mode of action, indication for use, and clinical guidelines. Substances having a high degree of toxicity and not recommended for use on cutaneous ulcers, such as chlorhexidine [1, 2], hexa- chlorophene [3, 4], or surfactants [5], will not be discussed. Other substances (e.g., hydrogen peroxide) will be mentioned, although their use on cutaneous ulcers is controversial.

11.2 Oxidizing Agents

11.2.1 Hydrogen Peroxide

The active oxidant form, which has a detrimental effect on living tissues, is not hydrogen peroxide itself but rather the free hydroxyl radicals formed by its decomposition [6]. Hydrogen peroxide, in concentrations of 3–6%, is effective against bacteria. At higher concentrations it kills other organisms, including spores. Howev- er, it should not be used on tissues at those concentrations, since it may cause irritating burns to skin and mucous membranes [7].

In fibroblast culture studies, 3% hydrogen peroxide solution was more toxic to fibroblasts than to bacteria [8]. It inhibited keratinocyte migration and proliferation when used in low concentrations [9].

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A few studies have suggested that hydrogen peroxide has a beneficial effect on wound healing. Tur et al. [10] showed that topical use of hydrogen peroxide on ischemic ulcers of guinea pigs might enhance blood recruitment to the ulcer site and adjacent skin, as well as to distant sites. Nevertheless, in view of the toxicity in- volved, in most cases the use of hydrogen peroxide on cutaneous ulcers should be avoided.

Its use may be considered in difficult-to-heal ulcers that other modes of treatment have failed to clean adequately.

Recently, a topical preparation (Crystacide®) was developed in which 1% hydrogen peroxide is integrated in a network of lipid crystals com- bined with two monoglycerides – monoleurine and monomyristine. This product has been shown to have some antibacterial activity [11].

This form of oxidative agent may reduce the toxicity against host tissue while maintaining its antibacterial effect. More studies are required to evaluate whether this type of preparation may have beneficial effects on cutaneous ulcers.

11.2.2 Potassium Permanganate

Potassium permanganate is available as purple crystals, soluble in water. The preparation is used for soaking the treated area, or a cloth soaked in potassium permanganate may be applied repeatedly to the wound. The solution should be diluted to a concentration of 0.01%

(1 in 10,000 solution) so as to achieve a light pink color [12].

Higher concentrations of potassium permanganate are not recommended and may damage the ulcer tissue. Very high concentrations of potassium permanganate may be caus- tic.An excessively high concentration can be de- tected, since it stains the nails. Reports of fatal- ities following ingestion of potassium permanganate attest to its toxicity [13, 14].

11.3 Iodines

Iodine in its various chemical forms has been used for two centuries in the management of

wounds. Iodine can penetrate cell walls of microorganisms and is active against bacteria, viruses, and fungi. Its effect is attributed to the disruption of proteins and nucleic acids [15].

11.3.1 Povidone-Iodine

Povidone-iodine is a complex of iodine with povidone and is the most widely used form of iodine as an antiseptic. This complex provides a reservoir of iodine, with a gradual release of iodine to the target tissue. For management of wounds or chronic skin ulcers, povidone-iodine is available as a solution or as an ointment, in concentrations of 4–10% [16].

The principles of management of cutaneous ulcers (as described in Chap. 20) also apply to povidone-iodine. In solution form, it should be used for secreting wounds, while the ointment is intended for dry wounds, or for chronic ulcers covered by dry crust. The effectiveness of povidone-iodine wanes after a few hours, so the dressing needs to be replaced twice daily [17].

At lower concentrations, povidone-iodine is also available as a surgical scrub or skin cleans- er, with 0.75% iodine incorporated in a deter- gent base [18].

Several studies have demonstrated the po- tential toxicity of povidone-iodine to human keratinocytes and fibroblasts [8, 19, 20]. One- percent povidone-iodine was found to be toxic to human fibroblasts when added to in vitro cultures. However, in a concentration of 1 : 1000, bactericidal activity was still demonstrated, with no evidence of human-fibroblast toxicity [8].

Contact sensitivity may occur following the use of povidone-iodine [21–23], although it is less frequent compared with neomycin, a commonly used topical antibiotic [24]. Acute generalized urticaria-angioedema has been reported following the topical use of povidone-iodine [25], and anaphylaxis has occurred following vaginal application [26]. In any patient, inflam- matory changes of the skin around the ulcer, accompanied by itching, necessitate immediate discontinuation of the treatment.

Numerous clinical trials have been per- formed on the effectiveness of povidone-iodine

Chapter 11 Topical Antibacterial Agents 152

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on cutaneous ulcers, yielding conflicting results, several of which are discussed below.

Pierard-Franchimont et al [27] compared the effect of povidone-iodine solution with hydrocolloid with that of hydrocolloid alone, as well as with elastic stockings. There was no statistically significant difference in wound healing between the two groups after eight weeks of treatment.

A unique study was published in 2002 by Fu- mal et al. [28], involving 51 patients who each had at least two chronic leg ulcers of similar nature. The wound beds were described as dull and dark red with dispersed yellowish foci. In 17 of the patients, one of the two ulcers was treated with hydrocolloid dressings and saline rinsing three times a week, while the second ulcer was treated similarly with povidone-iodine solution applied underneath the hydrocolloid dressing. They measured the surface areas of the ulcers after three and six weeks of treatment. The use of povidone-iodine significantly improved the rate of healing and lowered the time required to achieve complete healing of the ulcers.

The effect of povidone-iodine dressings was compared with that of hydrocolloid dressings.

No statistically significant difference in healing was found between the two groups after 56 days of treatment [29].

11.3.2 Other Iodine Compounds

Other formulations of iodine have been stud- ied, such as iodoform, a slow-release iodine preparation [16], and cadexomer-iodine gel, which contains microspheres that are intended to absorb bacteria and exudate, while slowly releasing iodine into the wound. This issue is de- tailed in Chap. 8.

Toxicity of Iodine Compounds.As stated in the previous chapter, there is not always a clear concordance between in vitro results and the actual clinical outcome when antiseptic substances are applied to human chronic ulcers.

This is especially applicable to advanced forms of iodine compounds such as cadexomer-iodine®. Recent evidence suggests that low-

concentration slow-release formulations of iodine do not present a significant risk of toxicity. Avoiding their use based on the results of in vitro studies of the past, therefore, is evident- ly not justified [30, 31].

11.4 Chlorines

Hypochlorites are common chlorine-releasing compounds, widely used in the management of cutaneous ulcers. They have a wide spectrum of antimicrobial activity against bacteria, fungi, and viruses.

It is not clear how chlorine compounds exert their antimicrobial activity. Possible mechanisms involve the denaturation of proteins, the inactivation of nucleic acids, and the inactivation of certain key enzymatic reactions within the cell [15, 32].

Chlorine compounds commonly used are:

5Eusol

5Dakin’s solution 5Milton’s solution

Eusol (Edinburgh University Solution of Lime) consists of a chlorinated lime and boric-acid solution containing 0.25% chlorine [33]. Sodi- um hypochlorite solutions such as Dakin’s solution or Milton’s solution, diluted up to 0.5%

of available chlorine [34], are used on cutaneous ulcers.

All chlorine compounds were toxic to human tissue when tested on keratinocyte or fibroblast cultures [19, 20]. When applied to open wounds that were healing by secondary intention, Eusol was shown to prolong the acute in- flammatory response [35]. Brennen et al. [36]

demonstrated the pronounced detrimental effect of Eusol on granulation tissue in animal models following its application to healing tissue. In light of the above, chlorine compounds should be used on cutaneous ulcers for limited periods of time only, the purpose being to cleanse the ulcer bed.

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11.5 Silver

11.5.1 General Comments

Silver and silver compounds, known for their antibacterial effect, have been used in medicine since the nineteenth century [37, 38]. Silver nitrate and later silver sulfadiazine have been used in recent decades as the treatments of choice for burns.

The bacteriostatic properties of silver ions were evaluated in vitro by Deltch et al. [39] using a woven nylon cloth coated with metallic silver. The antibacterial effects were shown to be proportional to the concentration of silver ions around the organisms tested. In vivo tests [40–42] have demonstrated the antibacterial effect of silver in a variety of organisms, includ- ing Staphylococcus aureus, Esherichia coli, Pseudomonas aeruginosa, and Proteus mirabi- lis. The bacteriocidal action of silver is propor- tional to the amount of silver and its rate of release [38]. Silver denatures nucleic acids, there- by inhibiting bacterial replication [43, 44].

Compared to the situation with antibiotic substances, bacteria show a relatively low ten- dency to develop resistance to silver or silver compounds [45, 46]. Furthermore, silver is ef- fective against Candida species [38, 47] by interfering with the normal synthesis of the yeast cell wall. Wright et al. reported the effectiveness of topical silver against fungal infections in burns [48].

There is also evidence that silver ions can damage host tissue by interfering with fibroblast proliferation, thus possibly impairing wound-healing processes [49–51]. Data on the possible toxicity of silver sulfadiazine are discussed below.

Currently, silver compounds may be used in the treatment of cutaneous ulcers in the form of silver sulfadiazine. Novel modes of dressings incorporating silver have been introduced, such as Actisorb (discussed in Chap. 8).

11.5.2 Silver Sulfadiazine

Silver sulfadiazine (SSD) is prepared as a water- soluble cream in a concentration of 1%. It is

composed of silver nitrate and sodium sulfadiazine, both having antibacterial qualities [52].

SSD is commonly used in the management of burns and cutaneous ulcers. It seems to be effective against a wide range of pathogenic bacteria, including Staphylococcus aureus, Esh- erichia coli, Proteus, Enterococci and, to some extent, Pseudomonas strains [52–54]. However, the presence of Pseudomonas strains resistant to silver sulfadiazine has been documented [54]. SSD has some effect against methicillin- resistant Staphylococcus aureus [55, 56]. As is the case with other silver compounds, SSD also shows a certain degree of activity against some yeast and fungi [52, 53].

Contraindications.In cases of documented sensitivity to sulfa compounds or G6PD defi- ciency, SSD is contraindicated. In addition, since sulfonamides are known to be possible inducers of kernicterus, silver sulfadiazine is contraindicated in pregnancy or during the first 2 months of life.

Adverse Effects.When SSD is used for cutaneous ulcers, the most common side effect is allergic contact dermatitis, manifested by red- ness and itching [57, 58]. In most cases, the sensitivity is to the vehicle component and not to the active ingredient. Usually, these reactions are well tolerated and can be easily managed by avoiding topical application or by using steroid topical preparations, if needed. Other adverse effects of SSD have been reported following its use for widespread burns, including transient leukopenia [59, 60] and methemoglobinemia [61].

Silver Sulfadiazine and Cutaneous Ulcers.

SSD is applied twice a day to cutaneous ulcers, and care must be taken to remove all traces of the substance from the ulcer bed when chang- ing the dressing. Following the topical use of SSD a proteinaceous gel forms over the wound surface area, which must be distinguished from a purulent discharge.

Silver Toxicity.Not surprisingly, as with other antiseptic compounds, the antimicrobial activity of silver is associated with some degree of toxicity to host tissues. In vitro studies of kera-

Chapter 11 Topical Antibacterial Agents 154

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tinocyte cultures have demonstrated significant toxicity against human keratinocytes [20, 51]. In vivo studies on the effect of SSD on epithelial- ization have shown contradictory results. In most studies, in fact, SSD has not been found to delay epithelialization [62–64]. A significant delay in wound contraction following the use of SSD has been documented [64, 65].

Clinical Studies.Several clinical studies on cutaneous ulcers comparing the effect of SSD with that of saline cleansing plus non-adherent dressing showed no statistically significant dif- ferences in wound healing [66]. However, other studies did show a beneficial effect of SSD.

Bishop et al. [67] conducted a prospective, randomized study on the healing of venous ulcers, comparing the effect of SSD with that of tripeptide-copper complex or placebo. SSD was found to be significantly more effective than the other two preparations in reducing the ulcer area.

Van den Hoogenenband documented better healing results of chronic leg ulcers treated by split-thickness skin grafting when silver sulfadiazine had been applied over a period of five days before the grafting procedure [68].

The unique study quoted above in reference to povidone-iodine [28] also included an arm involving the use of SSD: In 17 of the patients who had two chronic leg ulcers of similar nature, one of the two ulcers was treated with hydrocolloid dressings and saline rinse, while the other ulcer was treated similarly, but with the addition of SSD applied underneath the hydrocolloid dressing. They measured the surface areas of the ulcers after three and six weeks of treatment. Those ulcers treated with SSD showed a modest improvement over those treated with hydrocolloid alone.

Final Comment.The information presented above should be considered when SSD is applied; it should be used for only a limited period of time. Most of the antibacterial substances in this chapter should be used for limited periods of time, basically with the aim of cleansing the wound and protecting against infection.

Once the ulcer is clean, more definitive treatment should be used.

Examples of dressings containing silver:

5Acticoat with Silcryst® nanocrystals – Smith & Nephew

5Actisorb plus® – Johnson & Johnson (a charcoal dressing)

5Actisorb silver 220® – Johnson &

Johnson (a charcoal dressing) 5Aquacel AG® – Convatec 5Contreet foam® – Coloplast 5Contreet hydrocolloid® – Coloplast

11.6 Other Antiseptics

11.6.1 Antiseptic Dyes

Antiseptic dyes have been used for many years to disinfect wounds and chronic skin ulcers [69]. Substances such as gentian violet (crystal violet) or brilliant green are known to have antibacterial properties against gram-positive and gram-negative bacteria. Gentian violet was reported to be effective in the eradication of methicillin-resistant Staphylococcus aureus strains from pressure ulcers [70]. Brilliant green was also shown to be especially effective against dermatophytes and yeasts [69].

However, both substances have been found to be potent inhibitors of wound healing. Neid- ner at al. [71] found that both dyes reduced granulation tissue formation to 5% of the normal amount. There are also reports of significant tissue damage caused by gentian violet, and of its inhibitory effect on wound healing [72–74]. In addition, necrotic skin reactions have been documented following the use of gentian violet [75], and there have been reports of a possible carcinogenic effect of antiseptic dyes [75, 76]. Therefore, these dyes are contraindicated in the treatment of cutaneous ulcers.

Among other antiseptic dyes are eosin, a flu- orescent dye, used in a concentration of 0.5%, which has an antibacterial effect and does not interfere with wound healing [69]. Fuchsin is a mixture of rosaniline and pararosaniline. It has an antimycotic effect [69] and is used only in the form of ‘solutio castellani cum colore’.

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There are no evidence-based clinical data regarding the use of eosin or fuchsin on cutaneous ulcers.

11.6.2 Burow’s Solution

Burow’s solution, named after Karl August von Burow (1809–1874), has been used since the nineteenth century [77]. At present, it is employed mainly as a local otological preparation for the treatment of discharging ear. In its diluted form, it may be applied to the skin as a wet dressing to oozing areas, including secreting cutaneous ulcers [78, 79]. It is composed of aluminum acetate, prepared from aluminum sulfate and acetic acid, and purified water. It contains about 0.65% aluminum salts [78]. The solution must be freshly prepared and used within a few days.

The solution is said to have an antiseptic effect, which may be attributed to its acidity. Being hygroscopic, it can absorb secretions. This qual- ity further supports its use on secreting cutaneous ulcers.

In vitro studies have demonstrated that Burow’s solution may have a certain inhibitory effect on bacteria such as Pseudomonas aerugi- nosa, Staphylococcus aureus, and Proteus mi- rabilis [80], as well as on species of fungi and yeasts [81].

In a double-blind, randomized study comparing the effect of Burow’s solution with that of gentamicin sulfate in the treatment of otor- rhea, no significant difference was observed between the preparations. In contrast to gentamicin, however, development of resistant organisms was not found following treatment with Burow’s solution [82]. At present, there are no adequate data regarding the efficacy of Burow’s solution on cutaneous ulcers.

11.7 Conclusion

Under certain circumstances, one may consider using the substances discussed in this chapter to cleanse cutaneous ulcers. Be aware, however, of possible damage to the wound tissues, or

possible impairment of wound healing that may follow the use of these substances.

There may be a price to pay in order to control infection and achieve a cleaner ulcer.

Therefore, this treatment is meant to be used for only short periods of time, and once the ulcer is clean, other forms of treatment should be employed.

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